ZA200209997B - Indole derivatives useful for the treatment of CNS disorders. - Google Patents
Indole derivatives useful for the treatment of CNS disorders. Download PDFInfo
- Publication number
- ZA200209997B ZA200209997B ZA200209997A ZA200209997A ZA200209997B ZA 200209997 B ZA200209997 B ZA 200209997B ZA 200209997 A ZA200209997 A ZA 200209997A ZA 200209997 A ZA200209997 A ZA 200209997A ZA 200209997 B ZA200209997 B ZA 200209997B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- compound according
- disorder
- bond
- compounds
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims description 15
- 150000002475 indoles Chemical class 0.000 title claims description 3
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 208000015114 central nervous system disease Diseases 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 78
- 238000000034 method Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- -1 cyano, nitro, amino Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 208000019695 Migraine disease Diseases 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 6
- 206010027599 migraine Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000003441 thioacyl group Chemical group 0.000 claims description 5
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 230000016571 aggressive behavior Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000000164 antipsychotic agent Substances 0.000 claims description 4
- 208000010877 cognitive disease Diseases 0.000 claims description 4
- 208000019906 panic disease Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000007958 sleep Effects 0.000 claims description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- BRDOSVKYLZAYTP-UHFFFAOYSA-N 3-[3-[1-(1H-indol-5-yl)piperidin-4-yl]propyl]-2lambda6-thia-3-azatricyclo[6.3.1.04,12]dodeca-1(11),4,6,8(12),9-pentaene 2,2-dioxide Chemical compound C1=CC(S(=O)(=O)N2CCCC3CCN(CC3)C=3C=C4C=CNC4=CC=3)=C3C2=CC=CC3=C1 BRDOSVKYLZAYTP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- WAYXBKJPXZKSMK-UHFFFAOYSA-N C1=CC(S(=O)(=O)N2CCCN3CCN(CC3)C=3C=C4C=CNC4=CC=3)=C3C2=CC=CC3=C1 Chemical compound C1=CC(S(=O)(=O)N2CCCN3CCN(CC3)C=3C=C4C=CNC4=CC=3)=C3C2=CC=CC3=C1 WAYXBKJPXZKSMK-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 38
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 36
- 102000005962 receptors Human genes 0.000 description 30
- 108020003175 receptors Proteins 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229960003638 dopamine Drugs 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 230000002152 alkylating effect Effects 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- 102000003962 Dopamine D4 receptors Human genes 0.000 description 5
- 108090000357 Dopamine D4 receptors Proteins 0.000 description 5
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 229910000086 alane Inorganic materials 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 230000000561 anti-psychotic effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- MZILCLREQQTZJP-UHFFFAOYSA-N 5-piperazin-1-yl-1h-indole Chemical compound C1CNCCN1C1=CC=C(NC=C2)C2=C1 MZILCLREQQTZJP-UHFFFAOYSA-N 0.000 description 3
- ULMINHJMQWBDGD-UHFFFAOYSA-N 5-piperidin-4-yl-1h-indole Chemical class C1CNCCC1C1=CC=C(NC=C2)C2=C1 ULMINHJMQWBDGD-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical class C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000010807 negative regulation of binding Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000004031 partial agonist Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 3
- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- FDCMYMMFTWOSAT-UHFFFAOYSA-N 3-(3-bromopropyl)-2lambda6-thia-3-azatricyclo[6.3.1.04,12]dodeca-1(11),4,6,8(12),9-pentaene 2,2-dioxide Chemical compound C1=CC(S(N2CCCBr)(=O)=O)=C3C2=CC=CC3=C1 FDCMYMMFTWOSAT-UHFFFAOYSA-N 0.000 description 2
- UGMBIAPMJXMUOS-UHFFFAOYSA-N 5-(1,2,3,6-tetrahydropyridin-4-yl)-1h-indole Chemical compound C1NCCC(C=2C=C3C=CNC3=CC=2)=C1 UGMBIAPMJXMUOS-UHFFFAOYSA-N 0.000 description 2
- DEEIDJWDLYITNC-UHFFFAOYSA-N 6-piperazin-1-yl-1h-indole Chemical compound C1CNCCN1C1=CC=C(C=CN2)C2=C1 DEEIDJWDLYITNC-UHFFFAOYSA-N 0.000 description 2
- 206010001488 Aggression Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 2
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 2
- 229960004170 clozapine Drugs 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 229960003368 croscarmellose sodium type a Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 2
- 229960005417 ketanserin Drugs 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 2
- 229950001675 spiperone Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 210000003568 synaptosome Anatomy 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DLBPTOMGZXBZOX-UHFFFAOYSA-N 1,2-thiazole 1,1-dioxide Chemical compound O=S1(=O)C=CC=N1 DLBPTOMGZXBZOX-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MIMYTSWNVBMNRH-UHFFFAOYSA-N 1h-indol-6-amine Chemical compound NC1=CC=C2C=CNC2=C1 MIMYTSWNVBMNRH-UHFFFAOYSA-N 0.000 description 1
- SZQUPQVVCLFZLC-UHFFFAOYSA-N 2-[benzyl(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC1=CC=CC=C1 SZQUPQVVCLFZLC-UHFFFAOYSA-N 0.000 description 1
- HCGYMSSYSAKGPK-UHFFFAOYSA-N 2-nitro-1h-indole Chemical class C1=CC=C2NC([N+](=O)[O-])=CC2=C1 HCGYMSSYSAKGPK-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- FVSMIZSQPPDGCK-UHFFFAOYSA-N 3-[3-[4-(1H-indol-6-yl)piperazin-1-yl]propyl]-2-thia-3-azatricyclo[6.3.1.04,12]dodeca-1(11),4,6,8(12),9-pentaene Chemical compound C1=CC(N(CCCN2CCN(CC2)C=2C=C3NC=CC3=CC=2)S2)=C3C2=CC=CC3=C1 FVSMIZSQPPDGCK-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 108091005482 5-HT4 receptors Proteins 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
- SKTFQHRVFFOHTQ-UHFFFAOYSA-N 8-bromo-1,3-dimethyl-7h-purine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Br)=N2 SKTFQHRVFFOHTQ-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002869 Anxiety symptoms Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- ONTRFMGLHYDVMR-UHFFFAOYSA-N C1=CC(S(=O)(=O)N2CCCC=3CCN(CC=3)C=3C=C4C=CNC4=CC=3)=C3C2=CC=CC3=C1 Chemical compound C1=CC(S(=O)(=O)N2CCCC=3CCN(CC=3)C=3C=C4C=CNC4=CC=3)=C3C2=CC=CC3=C1 ONTRFMGLHYDVMR-UHFFFAOYSA-N 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000001653 corpus striatum Anatomy 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- RCFDIXKVOHJQPP-UHFFFAOYSA-N furo[2,3-b]pyridine Chemical compound C1=CN=C2OC=CC2=C1 RCFDIXKVOHJQPP-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical class N1(CCCC=C1)* 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Description
INDOLE DERIVATES USEFUL FOR THE TREATMENT OF CNS DISORDERS
The present invention relates to a novel class of indole derivatives having affinity for the dopamine D4 receptor. The compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. The compounds also have affinity for the 5-HT,4 receptor.
Dopamine D, receptors belong to the dopamine D, subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of npeuroleptic drugs, which primarily exert their effect via antagonism of D, receptors, are known to be due to D, receptor antagonism in the striatal regions of the brain. However, dopamine Dj, receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D; receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526, and Sanner Exp.
Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which were postulated to be selective Dy receptor antagonists (L- 745,879 and U-101958), have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613- . 620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a : 30 silent antagonist (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D, antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142:78-84).
Furthermore, evidence for a genetic association between the "primarily inattentive" subtype of attention deficit hyperactivity disorder and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol.
Psychiat. 2000, 5, 531-536). This clearly indicates a link between the dopamine D, receptor and attention deficit hyperactivity disorder and ligands affecting this receptor may be useful for the treatment of this particular disorder.
Various effects are known with respect to compounds, which are ligands at the different serotonin receptor subtypes. As regards the 5-HT»4 receptor, which was previously referred to as the 5-HT}; receptor, the following effects have been reported e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119.), reduction of the negative symptoms of schizophrenia and of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HTja antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; "Migraine — Current trends in research and treatment”; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al, Psychopharmacology 1985, 86, 303-305 and
Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).
Some clinical studies implicate the 5-HT, receptor subtype in aggressive behaviour.
Furthermore, atypical serotonin-dopamine antagonist neuroleptics, have 5-HT, receptor antagonistic effect in addition to their dopamine blocking properties, and have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents. 1998, 8(4), . 350-351). . Recently, evidence has also accumulated which support the rational for selective 5-HT24 antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al
Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS
Investigational Drugs 2000, 2(1), 22-24).
Accordingly, dopamine Dj receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at dopamine D, and 5-HT,4 receptors may have the further benefit of improved effect on positive and negative symptoms in schizophrenia, including depressive and anxiety symptoms.
Dopamine D, ligands related to the compounds of the invention are known from WO 98/28293. The indane and dihydroindole derivatives disclosed herein have the general formula
R®
A—X 4 N——(CHa)y——W ——— (CH), Re \ 2 ES
Y rR?
R2 wherein A is an indole and Y is a group completing an indane or a dihydroindole and the other substituents are as defined in the application.
EP 722 942 claim compounds having the formula =) 4 eT
Ri ) \
N wherein Q is a chain and Z is CO, SO; or SO and the other substituents are as defined in the application. The compouds are said to have serotonin agonistic and -antagonistic activities.
The compounds are in particular said to bind to 5-HT> and D, receptors.
Other dopamine D, ligands, wherein the indane or dihydroindole is replaced by a pyrrolo[2,3-b]pyridine, a benzimidazole or a furo[2,3-b]pyridine, are described in WO 94/20497, WO 94/22839 and US 5,700,802.
The object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D4 receptor, in particular such compounds with combined effects at the dopamine Dj, receptors and the 5-HT;, receptor.
A further object of the invention is to provide compounds with no or only low affinity for alpha-1 adrenergic receptors.
Accordingly, the present invention relates to novel compounds of formula I
R’ R®
RS Rr’
SN ) " ¢ —X’ N—(CH2)q——W —(CHz)q—Z—N
N SF \/ \, R11 / ‘
R® R
R12 RY } ® wherein Y is CO, CS, SO, SO, or CH; Z is CO, CS, SO, SO, or CH,; provided that only one of Y and Z is CO, CS, SO or SO»;
Wisabond, O, S, CO, CS, SO or SO; n is 0-5, m is 0-5 and n + m is 1-6; provided that when Wis QO or S,thenn>2 and m > 1, when W is CO, CS, SO or SO,, then n > land m >1;
X is N or CH and the dotted line represents no bond, or X is C and the dotted line represents abond;
one of R!, R?, R? and R* forms a bond to X and the others of R!, R%, R*and R* and R® and
R’ - R'? are selected from hydrogen, halogen, cyano, nitro, amino, C;¢-alkyl-amino, di-( C,. ¢-alkyl )-amino, C,¢-alkyl, C,¢-alkenyl, Cy ¢-alkynyl, Cig alkoxy, C,¢-alkylthio, hydroxy, : Ci-¢-alkyl substituted with hydroxy or thiol, Cs.g-cycloalkyl, C3 g-cycloalkyl-C,¢-alkyl, acyl, 5 thioacyl, trifluoromethyl, trifluoromethylsulfonyl and C,¢-alkylsulfonyl; and
R®is hydrogen, C,¢-alkyl, Cy4-alkenyl, C,¢-alkynyl, C;¢-alkyl substituted with hydroxy or thiol, C;s-cycloalkyl, Css-cycloalkyl-Ci-alkyl, acyl, thioacyl, trifluoromethylsulfonyl and
Ci. alkylsulfonyl; or pharmaceutically acceptable salts thereof.
In a first particular embodiment, the present invention relates to compounds wherein Z is CH; and Y is SO,.
In a second embodiment, the invention relates to such compounds wherein one of RR?
R? and R* forms a bond to X and the others of R!, R%, R® and R* and R® and R” - R'? are selected from hydrogen, halogen, cyano, nitro, amino, C¢-alkyl, Cg alkoxy, Ci- alkylthio, hydroxy, and trifluoromethyl andR® is hydrogen, C,-alkyl, or C,¢-alkylcarbonyl.
In a third embodiment, the present invention relates to compounds wherein R? or R? forms a bond to X.
In a fourth embodiment, the invention relates to such compounds wherein X is N.
In a fifth embodiment, the invention relates to such compounds wherein X is C.
In a sixth embodiment, the invention relates to such compounds wherein X is CH.
In a seventh embodiment, the invention relates to such compounds wherein W is a bond and n . + mis 1 to 4, in particular 3.
Specific compounds according to the invention are
2-{3-[4-(1H-Indol-5-yl)piperazin-1-yl]propan-1-yl}-2H-naphtho[1,8-cd]isothiazole 1,1- dioxide, 2-{3-[4-(1H-Indol-6-yl)piperazin-1-yl]propan-1-yl}-2H-naphtho[1,8-cd}isothiazole1,1-dioxide, 2-{3-[1 _(1H-Indol-5-y1)-3,6-dihydro-2 H-pyridin-4-ylJpropan- 1-y1}-2H-naphtho[1,8- cd]isothiazole 1,1-dioxide ’ 2-{3-[1-(1H-Indol-5-yl)piperidin-4-yl]propan-1-yl}-2 H-naphtho[1,8-cd]isothiazole 1,1- dioxide or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the invention have been found to show high affinity for dopamine Dy receptors and to be partial agonists or antagonists at dopamine Dy receptors. The compounds also show affinity for serotonergic 5-HT>4 receptors.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia and other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, aggression, cognitive disorders, side effects induced by conventional antipsychotic agents, migraine, attention deficit hyperactivity disorder and in the improvement of sleep.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
The compounds of general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C,¢-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2- methyl-2-propyl,2-methyl-1-propyl, pentyl and hexyl.
Similarly, C,¢-alkenyl and C,s-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The terms Cig¢-alkoxy, Cig-alkylthio, C;¢-alkylsulfonyl, C,¢-alkylamino, C.- alkylcarbonyl, etc. designate such groups in which C,¢-alkyl is as defined above.
The term Cs-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
Halogen means fluoro, chloro, bromo or iodo.
As used herein the term acyl refers to a formyl, C;.¢-alkylcarbonyl, arylcarbonyl, aryl-Cj.¢-alkylcarbonyl, Cs.g-cycloalkylcarbonyl or a Cs.s-cycloalkyl-Cis-alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
The term aryl refers to a carbocyclic aromatic group, such as phenyl or naphthyl, in particular phenyl, including methyl substituted phenyl or napthyl.
The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, . mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8- ) halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of : solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05 - 500 mg and most preferably about 0.1 to 50 mg of the active compound of the invention.
The compounds of the invention may be prepared as follows: 1) Alkylating a piperazine, piperidine or tetrahydropyridine of formula II with an alkylating derivative of formula III:
RY R®
Rr!
R® Rr? R® =a WD, [ ST NH EWG y Ne / Y. CC) R10
LL
R12 RM an (Im) wherein RR? X,Z,Y, n,m, W and the dotted line are as previously defined, and L is a leaving group such as e.g. halogen, mesylate or tosylate; : 2) Reductive alkylation of an amine of formula IT with a reagent of formula IV:
rR rE
R!
R® Rr? ; Rr? —7 VA § )
L TT N—H 5 = ® A WE) wherein R!-R'%, X, Z, Y, n, m, W and the dotted line are as previously defined, and E is either an aldehyde or an activated carboxylic acid group; 3) Alkylating a compound of formula VI with an alkylating derivative of formula V:
Rr’ RS
R!
R® RZ [ 7 LE, / N—(CHz)y—W—(CHz)mst—L y § J) ) [ Ail WT (LH) mem
N XN ~~ \, CO) R10 le Re v) VD
R12 rR wherein R'-R'2, X, Y, n, m, W and the dotted line are as previously defined and L is a leaving group such as e.g. halogen, mesylate or tosylate, and Uis NHor N"; 4) Reducing the tetrahydropyridinyl double bond in derivatives of formula VII:
R’ R® rR?
RS R2 9 \ = I J §) ) lL NCH WT GHZ
AA y §) i”
L R* - Rr"? Rr . (VID wherein R'-R'%, Z, Y, n, m and W are as previously defined,
5) Reducing the amide carbonyl in a compound of formula VIII:
Rr RE rR?
R® R? ; R® \ Z 4 \§ LC) } lL TI. N——C~—(CHa)ps——W——(CH)m—Z—N,
N Xx Nv \, QC) R10 le R*
R12 Rr (vin wherein R!-R"?, X,Y, Z,n, m, W and the dotted line are as previously defined, 6) Reducing the amide carbonyl in a compound of formula IX:
R’ R®
RY
R® Rr? ; : 0 R® [ ~ Ev N— (CHa); —W—(CH,) I N CJ
I 2h WU) 7
Ny — \ $C) R10 le Rr
R12 RY ax) wherein R'-R'2, X, Y, n, m, W, and the dotted line are as previously defined; 7) Reductive alkylation of an amine of formula XI with a reagent of formula X:
R? R®
Rr?
R® Rr? RO —7
TX N—(CH_)y—W—(CHz)n—E u
ANI aw
Ls R*
R12 - . 0 xD wherein R!-R'?, X, n, m, W and the dotted line are as previously defined, and E is either an ) 15 aldehyde or an activated carboxylic acid group, Y' is CH, and U is NH, or; 8) Acylation of an amine of formula XI with a reagent of formula X:
Rr’ R®
R!
R® RZ, QC) RS \ = Ne 2h W—(CHz)y—E U
LL So V CO) xo
LT
® RY R™ xD wherein R'-R'2, X, n, m, W and the dotted line are as previously defined, and E is either an aldehyde or an activated carboxylic acid group, Y! is CH, , U is NH; whereupon the compound of Formula (J) is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The alkylation according to methods 1) and 3) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be performed at a fixed temperature, which is different from the boiling point, in one of the above mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (NMP), preferably in the presence of a base.
Some of the amines of formula (IT) are known from the literature or may be prepared analogously (see WO 98/28293, WO 94/20459 and US patent No. 5,576,319). Piperazines of formula (IT) may be prepared from nitroindoles by reduction of the nitro group to an aniline, which subsequently is subjected to piperazine synthesis by methods obvious to a chemist skilled in the art (see also Kruse et al. Red. Trav. Chim. Pays.Bas. 1988 107, 303- 309). Piperidines such as 5-(piperidin-4-yl)-1H-indoles may be prepared from the corresponding tetrahydropyridines (WO 94/20459). Alkylating reagents of formula (III) are : known from the literature (see Malleron et al. J. Med. Chem. 1991, 43, 2477-2483).
Alkylating reagents of formula (V) can be prepared by methods obvious to a chemist skilled in the art, and compounds of formula (VI) are commercially available or described in the literature.
The reductive alkylation according to methods 2) and 7) is performed by standard literature methods. The reaction can be performed in two steps, e.g. coupling of derivatives of ~~ - hh : formula (II/XT) and the reagent of formula (IV/X) by standard methods via the carboxylic acid chloride or by use of coupling reagents such as e.g. dicyclohexyl carbodiimide followed by reduction of the resulting amide with lithium aluminium hydride or alane. The reaction can also be performed by a standard one-pot procedure. Aldehydes or carboxylic ] : acids of formula (IV/X) can be prepared analogously to the synthetic sequence described ; for alkylating reagents of formula (ILI/V) but by the use of acetal protected haloalkanal or the corresponding protected carboxylic acid derivatives.
The alkylation according to method 3), where Y is CO, CS, SO or SO, is conveniently performed by reacting the nitrogen anion of (VI) with (V). The nitrogen anion of (VI) can be prepared in an inert organic solvent, e.g. dimethyl formamide (DMF), dimethylsulfoxide : (DMSO) or N-methylpyrrolidin-2-one (NMP), by the use of a strong base, e.g. NaH, before the alkylation.
The reduction of the double bond according to method 4) is generally performed by catalytic hydrogenation at low pressure (< 3 atm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH, in - trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.
Starting materials of formula (VII) may be prepared by methods 1), 3), 7) and §).
Reduction of amide groups according to methods 5) and 6) is most conveniently performed with lithinm aluminium hydride or alane in an inert organic solvent such as e.g. tetrahydrofuran (THF) or diethylether from 0 °C to reflux temperature. Starting materials of formula (VII) may be prepared by method 2), whereas starting materials of formula (IX) may be prepared by methods 1), 7) and 8). :
IR
I The acylation according to method 8) is conveniently performed by the use of coupling ~ reagents such as e.g. dicyclohexyl carbodiimide.
Amended Sheet — 2004-02-24
Experimental Section : Melting points were determined on a Biichi B-540 apparatus and are uncorrected. Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments.
Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with
IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50 X 4.6 mm YMC ODS-A with 5 um particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 7 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times R, are expressed in minutes. "H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRXS500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, g=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=muitiplet, b=broad. NMR signals corresponding to acidic protons are generally omitted. Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60, 40-60 mesh ASTM was used.
Preparation of intermediates
A, Alkylating reagents 2-(3-Bromopropan-1-yl)-2H-naphth[ 1, 8-cd]isothiazole 1,1-dioxide . A suspension of sodium hydride (4.1 g, 60% in mineral oil) and dimethyl formamide (250 ml) was kept at 20-23 °C followed by the addition of a solution of 2H-naphth[1,8- : cd]isothiazole 1,1-dioxide (20 g) in dimethyl formamide (250 mL). The resulting mixture was stirred at room temperature for 10 min followed by the addition of a solution of 1,3- dibromopropane (40 mL) in dimethyl formamide (100 mL) at a temperature of 10-12 °C.
The resulting mixture was stirred at room temperature for 30 min and poured onto ice. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (MgSOy,) and concentrated in vacuo. The crude product was : purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:4) to give the product as a crystalline compound (20.4 g). : B. Amines 5-(Piperazin-1-yl)-1H-indole
A mixture of 5-nitro-1H-indole (34 g), palladium on activated carbon (Pd 5 %, water 50 %) (2.5 g) and ethyl acetate was shaken at room temperature for 1.5 h under 3 atmospheres of hydrogen. The mixture was filtered and the solvent was removed in vacuo to yield a crystalline compound (28 g), which was dissolved in tetrahydrofuran (400 mL). The solution was subsequently added to a boiling mixture of N-benzyliminodiacetic acid (54.4 15g) and 1,1’-carbonyldiimidazole (82.4 g) in tetrahydrofuran (1100 mL), and the resulting mixture was boiled under reflux for 3 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/triethylamine 100:4) to give a white crystalline compound (57.5 g), which subsequently was dissolved in tetrahydrofuran (300 mL) and added to alane in tetrahydrofuran (500 mL) at 5-16 °C. The alane was prepared from lithium aluminium hydride (25 g) and concentrated sulphuric acid (32.3 g). The mixture was stirred at 5 °C for 45 min and subsequently quenched by the addition of water (50 mL), 15 % aqueous sodium hydroxide solution (25 mL) and water (125 mL). The mixture was dried (MgSOy), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate) to give a brown oily compound (44.9 g), which subsequently was dissolved in methanol (1000 mL) and added ammonium formate (150 g) and palladium on activated carbon (Pd 5 %, water 50 %) (12 g). The mixture was boiled under reflux for 45 min, cooled, filtered and concentrated in vacuo. The residue was dissolved in . tetrahydrofuran/ethyl acetate and added brine and concentrated aqueous ammonia solution under cooling to give a basic reaction mixture. The two phases were separated and the ) aqueous phase was extracted an additional two times with tetrahydrofuran/ethyl acetate. The combined organic phases were washed with brine, dried (MgSO,) and concentrated in vacuo. The residue was crystallised from tetrahydrofuran/n-hetane to give the title compound (17.3 g). 6-(Piperazin-1-yl)-1H-indole ’ Prepared in a similar manner as 5-(piperazin-1-yl)-1H-indole starting from 6-amino-1H- indole (Brown et al. J. Am. Chem. Soc.. 1954, 76, 5149-5150). 5-(3,6-Dihydro-2H-pyridin-4-yl)-1H-indole
See WO 94/204509. 5-(Piperidin-4-yl)-1H-indole
A mixture of 5-(3,6-dihydro-2H-pyridin-4-yl1)-1H-indole (3.4 g), platinum oxide (0.2 g) and acetic acid (50 mL) was shaken at room temperature for 24 h under 3 atmospheres of hydrogen. The mixture was filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography on silicagel (eluent: 4 M ammonia in methanol) to give the title compound (1.3 g).
Preparation of the compounds of the invention
Example 1 1a, 2-{3-/4-(1H-Indol-5-yl)piperazin-1-yl]propan-1-yl}-2H-naphtho[1,8-cd]isothiazole 1,1- dioxide, hydrochloride
A mixture of 5-(piperazin-1-yl)-1H-indole (1.0 g), 2-(3-bromopropan-1-yl)-2H-naphth[1,8- cdlisothiazole 1,1-dioxide (1.6 g) and triethylamine (3.5 mL) in dimethyl formamide (10 mL) and butanone (100 mL) was boiled under reflux for 8 h. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/triethylamine 100:4) to give the crude product as an yellow oil (2.1 g).
The title compound was isolated as the hydrochloride salt from tetrahydrofuran as a white crystalline compound (1.6 g). Mp 275-278 °C. "H NMR (DMSO-dg): 2.30-2.45 (m, 2H); 3.35-3.80 (m, 10H); 4.05 (t, 2H); 6.45 (s, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.35 (s, 1H); 7.40- 7.50 (m, 2H); 7.60-7.75 (m, 2H); 7.95 (t, 1H); 8.25 (d, 1H); 8.35 (d, 1H); 11.15 (s, 1H); 11.45 (broad s). MS m/z: 447 (MH).
The following compounds were prepared in a similar manner: 1b, 2-{3-[4-(1H-Indol-6-yl)piperazin-1-yl]propan-1-yl}-2H-naphtho[1,8-cd]isothiazole 1,1- : dioxide, hydrochloride from 6-(piperazin-1-yl)-1H-indole and 2-(3-bromopropan-1-yl)-2H-naphth[1,8- cdlisothiazole 1,1-dioxide. Mp 214-215 °C. "H NMR (DMSO-d): 1.95-2.10 (m, 2H); 2.45- 2.60 (m, 6H); 3.05-3.15 (m, 4H); 3.95 (t, 2H); 6.25 (s, 1H); 6.75 (d, 1H); 6.85 (s, 1H); 7.10- 7.20 (m, 2H); 7.35 (d, 1H); 7.60 (d, 1H); 7.65 (t, 1H); 7.90 (t, 1H); 8.25 (d, 1H); 8.30 (d, 1H); 10.70 (s, 1H). MS m/z: 447 (MH). 1c, 2-{3-[1-(1H-Indol-5-yl)-3,6-dihydro-2H-pyridin-4-yl]propan-1-yl}- 2H-naphtho[1,8- cd]isothiazole 1,1-dioxide, hydrochloride from 5-(3,6-dihydro-2H-pyridin-4-yl)-1H-indole and 2-(3-bromopropan-1-yl)-2H- naphth[1,8-cd]isothiazole 1,1-dioxide. "H NMR (DMSO-dg):.2.00-2.10 (mn, 2H); 2.55-2.65 (m, 4H); 2.65-2.70 (m, 2H); 3.10 (s, 2H); 3.95 (t, 2H); 6.10 (s, 1H); 6.40 (s, 1H); 7.15 (d, 1H); 7.25 (d, 1H); 7.30-7.40 (m, 2H); 7.60 (s, 1H); 7.65 (d, 1H); 7.70 (t, 1H); 7.90 (t, 1H); 8.25 (d, 1H); 8.30 (d, 1H); 11.05 (s, 1H). MS m/z: 444 (MH+). 1d, 2-{3-[1-(1H-Indol-5-y))piperidin-4-yl[propan-1-yl}-2H-naphtho[1,8-cd]isothiazole 1,1- dioxide, hydrochloride from 5-(piperidin-4-yl)-1H-indole and 2-(3-bromopropan-1-yl)-2 H-naphth[1,8- cdlisothiazole 1,1-dioxide. LC/MS (m/z) 446 (MH+) 387; RT = 2.19; purity: 74%.
Pharmacological Testing
The compounds of the invention were tested in well-recognised and reliable tests. The tests were as follows:
Inhibition of the binding of PH]YM-09151-2 to human dopamine Dy receptors
By this method, the inhibition by drugs of the binding of [PHJYM-09151-2 (0.06 nM) to membranes of human cloned dopamine Dj; receptors expressed in CHO-cells is determined in vitro. Method modified from NEN Life Science Products, Inc., technical data certificate ’ PC2533-10/96.
Inhibition of the binding of [*’H]Ketanserin to 5-HT;,4 receptors
The compounds were tested with respect to their affinity for 5-HT4 receptors by determining their ability to inhibit the binding of PH]K etanserin (0.50 nM) to membranes from rat brain (cortex) in vitro. Method described in Sanchez et al. Drug Dev. Res. 1991, 22, 239-250.
The test results are shown in table 1:
Comp. D4-bind. 5-HT;5-bind.
No.
Table 1: Binding Data (ICs values in nM) or % inhibition of binding.
In general, the compounds of the invention have been found potently to inhibit the binding of PH]YM-0915 1-2 to dopamine Dy receptors. The compounds have also been tested in a functional assay described by Gazi et al. in Br. J. Pharmacol. 1999, 128, 613-620, and it was found that the compounds are antagonists or partial agonists at dopamine D4 receptors.
The compounds have also been found to inhibit the binding of [*’H]Ketanserin to 5-HT 2a ’ 25 receptors in vitro.
The compounds of the invention were also tested in the following tests:
Inhibition of binding of [*H]Spiperone to rat dopamine D; receptors -
By this method, the inhibition of drugs of the binding of [’H]Spiperone (0.5 nM) to dopamine
D, receptors in membranes from rat corpus striatum is determined in vitro. Method and results as described in Hyttel et al. J. Neurochem. 1985, 44, 1615-1622.
Inhibition of binding of [’H]Prazosine to rat alpha-1-receptors
By this method, the inhibition by drugs of the binding of [*H]Prazosin (0.25 nM) to alpha-1 receptors in membranes from rat brain is determined in vitro. Method modified from Hyttel et : - al J. Neurochem. 1985, 44, 1615-1622.
The compounds have no substantial or only weak affinity for the dopamine D; receptor.
Some of the compounds have no or only low affinity for the alpha-1 adrenergic receptor, which imply a low propensity to cause orthostatic hypotension, and no or only low sedative effect.
Inhibition of the uptake of [*H]Serotonin into whole rat brain synaptosomes : The compounds were tested with respect to their 5-HT reuptake inhibiting effect by measuring their ability to inhibit the uptake of [*H]serotonin into whole rat brain synaptosomes in vitro. The assay was performed as described by Hyttel
Psychopharmacology 1978, 60, 13.
Some compounds were shown to be 5-HT reuptake inhibitors. 5-HT reuptake inhibitors are well known antidepressant drugs. : :
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, Sther psychoses, anxiety disorders, such ‘as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, ~ depression, aggression, cognitive disorders, side effects induced by conventional : antipsychotic agents, migraine, attention deficit hyperactivity disorder and in the improvement of sleep. In particular, the compounds of the invention are considered useful _ Amended Sheet — 2004-02-24 13 y in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects. ’ Formulation Examples
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
Typical examples of recipes for the formulation of the invention are as follows: 1) Tablets containing 5.0 mg of the active compound calculated as the free base:
Active compound 5.0mg
Lactose 60 mg
Maize starch 30 mg
Hydroxypropylcellulose 24mg
Microcrystalline cellulose 19.2 mg
Croscarmellose Sodium Type A 24mg
Magnesium stearate 0.84 mg 2) Tablets containing 0.5 mg of the active compound calculated as the free base: } Active compound 0.5 mg
Lactose 46.9 mg
Maize starch 23.5 mg
Povidone 1.8 mg
Microcrystalline cellulose 14.4 mg
Croscarmellose Sodium Type A 1.8 mg ; Magnesium stearate 0.63 mg 3) Syrup containing per millilitre:
Active compound 25 mg
Sorbitol 500 mg
Hydroxypropylcellulose 15 mg
Glycerol 50 mg
Methyl-paraben 1 mg
Propyl-paraben 0.1 mg
Ethanol 0.005 ml
Flavour 0.05 mg
Saccharin sodium 0.5 mg
Water ad 1 ml 4) Solution for injection containing per millilitre:
Active compound 0.5 mg
Sorbitol 5.1 mg
Acetic Acid 0.05 mg
Saccharin sodium 0.5 mg
Water ad 1ml
Claims (4)
1. An indole derivative having the formula ° YY R® RS R' SN { ) { | —x’ N—(CHp)y—W —(CHa)p—2Z—N nN FF RS \ / \, () R10 1 R* R12 R11 ® wherein Y is CO, CS, SO, SO, or CHy; Z is CO, CS, SO, SO, or CHy; provided that only one of Y and Z is CO, CS, SO or SO; Wisabond, O, S, CO, CS, SO or SO; nis 0-5, mis 0-5 and n + m is 1-6; provided that when Wis Oor S, thenn>2 and m > 1, when Wis CO, CS, SO or SOy, thenn>1andm > 1; X is N or CH and the dotted line represents no-bond, or X is C and the dotted line represents a bond, one of R!, R%, R? and R* forms a bond to X and the others of Rl, R%L R*and R* and R® and R’ - R" are selected form hydrogen, halogen, cyano, nitro, amino, C;_¢-alkyl-amino, di-( C;. ¢-alkyl )-amino, Cys-alkyl, C,6-alkenyl, C,6-alkynyl, - Cs alkoxy, Ci¢-alkylthio, hydroxy,
C1.¢-alkyl substituted hydroxy or thiol, Cs s-cycloalkyl, Cs g-cycloalkyl-C;¢-alkyl, acyl, thioacyl, trifluoromethyl, trifluoromethylsulfonyl and C,.¢ alkylsulfonyl; and oo , R® is hydrogen, C,.¢-alkyl, C,¢-alkenyl, C, ¢-alkynyl, Cis-alkyl substituted hydroxy or thiol, ) Cs.g-cycloalkyl, Cs g-cycloalkyl-C,¢-alkyl, acyl, thioacyl, trifluoromethylsulfonyl and C;.¢ alkylsulfonyl; or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein Z is CH, and Y is SO,
3. A compound according to claim 1 or claim 2 wherein one of R!, R?, R> and R* forms a bond to X and the others of R!, rR? R? and R* and R® and R7 - R'? are selected from hydrogen, halogen, cyano, nitro, amino, Cy¢-alkyl, Cs alkoxy, C;¢-alkylthio, hydroxy and trifluoromethyl, R®is hydrogen, C,s-alkyl, Ci ¢-alkylcarbonyl and W is a bond oo
4. A compound according to any one of claims 1 to 3 wherein R? or R? form a bond to X.
10 . : )
5. A compound according to any one of claims 1 to 4 wherein X is N.
6. A compound according to any one of claims 1 to 4 wherein X is C.
7. A compound according to any one of claims 1 to 4 wherein X is CH. :
8. A compound according to any one of claims 1 to 7 wherein Wisabondann+ mis 1 to 4.
9. A compound according to claim 1 which is selected from 2-{3-[4-(1H-Indol-5-yl)piperazin-1-yl]propan-1-yl}-2H-naphtho[1,8-cd]isothiazole 1,1- dioxide, 2-{3-[4-(1H-Indol-6-y])piperazin-1-yljpropan-1-y1} -2H-naphtho[1,8-cd]isothiazolel 1- dioxide, 2-{3-[1-(1H-Indol-5-y1)-3,6-dihydro-2 H-pyridin-4-yl prop an-1-yl}-2H-naphtho(1,8- cd]isothiazole 1,1-dioxide, 2-{3-[1-(1H-Indol-5-yl)piperidin-4-yl]propan-1-yl} -2 H-naphtho[1,8-cd]isothiazole 1,1- dioxide ~ or a pharmaceutically acceptable acid addition salt thereof.
10. A pharmaceutical composition characterised in that it comprises a compound of any of . claims 1 to 9 in a therapeutically effective amount together with one or more pharmaceutically : acceptable carriers or diluents. Amended Sheet — 2004-02-24 - - E
]
11. Use of a compound of any of Claims 1 to 9 for the manufacture of a medicament useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, depression, aggression, cognitive disorders, side effects induced by conventional antipsychotic agents, migraine, attention deficit hyperactivity disorder and in the improvement of sleep. :
12. Use according to claim 11 wherein the anxiety disorder is generalised anxiety disorder, panic disorder or obsessive compulsive disorder.
13. A compound according to any of claims 1 to 9 for use in a method of treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, depression, aggression, cognitive disorders, side effects induced by conventional antipsychotic agents, migraine, attention deficit hyperactivity disorder and in the improvement of sleep comprising administration of a therapeutically acceptable amount of the compound.
14. A compound according to claim 13 wherein the anxiety disorder is generalised anxiety disorder, panic disorder or obsessive compulsive disorder.
15. A composition of claim 10 substantially as herein described with reference to any one of the illustrative examples. Amended Sheet — 2004-02-24
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200000957 | 2000-06-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200209997B true ZA200209997B (en) | 2003-12-10 |
Family
ID=8159567
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200209997A ZA200209997B (en) | 2000-06-19 | 2002-12-10 | Indole derivatives useful for the treatment of CNS disorders. |
Country Status (9)
Country | Link |
---|---|
US (1) | US20030162792A1 (en) |
BG (1) | BG107450A (en) |
BR (1) | BR0111763A (en) |
EA (1) | EA200300039A1 (en) |
IL (1) | IL153351A0 (en) |
IS (1) | IS6652A (en) |
PL (1) | PL359147A1 (en) |
SK (1) | SK512003A3 (en) |
ZA (1) | ZA200209997B (en) |
-
2001
- 2001-06-13 PL PL01359147A patent/PL359147A1/en not_active Application Discontinuation
- 2001-06-13 EA EA200300039A patent/EA200300039A1/en unknown
- 2001-06-13 SK SK51-2003A patent/SK512003A3/en unknown
- 2001-06-13 IL IL15335101A patent/IL153351A0/en unknown
- 2001-06-13 BR BR0111763-7A patent/BR0111763A/en not_active Application Discontinuation
-
2002
- 2002-12-09 IS IS6652A patent/IS6652A/en unknown
- 2002-12-10 ZA ZA200209997A patent/ZA200209997B/en unknown
- 2002-12-11 US US10/316,995 patent/US20030162792A1/en not_active Abandoned
-
2003
- 2003-01-08 BG BG107450A patent/BG107450A/en unknown
Also Published As
Publication number | Publication date |
---|---|
BR0111763A (en) | 2003-06-24 |
US20030162792A1 (en) | 2003-08-28 |
IL153351A0 (en) | 2003-07-06 |
IS6652A (en) | 2002-12-09 |
PL359147A1 (en) | 2004-08-23 |
EA200300039A1 (en) | 2003-04-24 |
BG107450A (en) | 2003-10-31 |
SK512003A3 (en) | 2003-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20040044007A1 (en) | Indoline derivatives | |
US7105543B2 (en) | 4-, 5-, 6- and 7-indole derivatives useful for the treatment of CNS disorders | |
AU2001279611A1 (en) | 4-, 5-, 6- and 7-indole derivatives useful for the treatment of CNS disorders | |
EP1294710B1 (en) | Indole derivatives useful for the treatment of cns disorders | |
EP1299384B1 (en) | Indole derivatives useful for the treatment of cns disorders | |
EP1299380B1 (en) | Indole derivatives useful for the treatment of cns disorders | |
AU2001273881A1 (en) | Indole derivatives useful for the treatment of CNS disorders | |
ZA200209997B (en) | Indole derivatives useful for the treatment of CNS disorders. | |
EP1468996B1 (en) | Indole derivatives for the treatment of CNS disorders | |
AU2002221576A1 (en) | 3-indoline derivatives useful in the treatment of psychiatric and neurologic disorders | |
ZA200209958B (en) | Indole derivatives useful for the treatment of CNS disorders. | |
MXPA02012149A (en) | Indole derivatives useful for the treatment of cns disorders |